Headaches are a common condition affecting millions of people in the United States alone. Headaches are generally classified into two categories: primary and secondary headaches. Primary headaches are those which are not associated with or caused by other diseases. They include migraines, tension-type headaches, cluster headaches, and other headaches such as stabbing, cough, exertional, hypnic, and thunderclap headaches. In contrast, secondary headaches are caused by an underlying structural problem in the head or neck. Secondary headaches include those attributed to head and/or neck trauma, cranial and/or cervical vascular disorders, non-vascular intracranial disorders, substance use, withdrawal from substance use, infection, physical disorders or psychiatric disorders.
Migraines are a chronic disorder characterized by recurring moderate to severe headaches. The World Health Organization has noted the disabling effect of migraines and reports that migraines are 19th among all causes of years lived with disability. In addition to headache pain, migraines are also associated with nausea, vomiting, photophobia, phonophobia, disturbances in taste, and disturbances in hearing. Migraines are typically unilateral and pulsating in nature and may last anywhere from between several hours to 3 days. Up to one-third migraine sufferers perceive an aura which can manifest itself as a transient visual, sensory, language, or motor disturbance. Such auras typically signal that a migraine will soon occur.
Because the causes of primary headaches (e.g., migraines) are highly varied and often unknown, treatment methods have been met with a lack of consistency and efficacy. For example, current migraine treatments can be characterized as abortive (i.e., treatments to abort current migraines) or preventative (i.e., treatments to prevent future migraines). Abortive treatments can be administered orally, nasally, or by injection. Triptans, such as IMITREX®, which specifically target serotonin, are commonly used as abortive migraine treatments. Examples of drugs used for abortive treatments include almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan, acetaminophen-isometheptene-dichloralphenazone, dihydroergotamine, ergotamine tartrate, ibuprofen, and aspirin-acetaminophen-caffeine. Preventative treatments are typically considered if migraines occur frequently (e.g., more than once per week) or if migraine symptoms are severe. Preventive treatments include beta-blockers (e.g., propranolol, timolol), calcium channel blockers (e.g., verapamil), antidepressants (e.g., amitriptyline, nortriptyline), antiseizure medications (e.g., gabapentin, topiramate, valproic acid), and BOTOX®. However, such treatments may be accompanied by unpleasant side effects. For example, side effects associated with verapamil include constipation, dizziness, nausea, fatigue, swelling of the ankles and low blood pressure. Side effects associated with IMITREX® include anxiety, burning, numbness or tingling of the skin, dizziness, drowsiness, muscle aches or cramps, nausea, neck stiffness, upset stomach, throat or sinus discomfort, tingling, tiredness, vomiting, and weakness.
Current cluster headache treatments have also met with varying success. Abortive treatments include oxygen, triptans, octreotide (e.g., sandostatin), local anesthtics (e.g., lidocaine), and dihydroergotamine. Though some treatments are more effective than others, treatments such as intranasal administration of lidocaine are not consistently effective in aborting cluster headache pain. Some preventative options are also available including calcium channel blockers, corticosteroids, lithium (e.g., Lithobid), nerve blocks (e.g., injecting an anesthetic and corticosteroid into the area around the occipital nerve), ergots (e.g., Ergomar), and melatonin. Again, such treatments are accompanied by unpleasant side effects including those typically associated with corticosteroids (e.g., corticosteroid withdrawal syndrome, hyperglycemia, insulin resistance, diabetes mellitus, osteoporosis, cataract, anxiety, depression, colitis, hypertension, ictus, erectile dysfunction, hypogonadism, hypothyroidism, amenorrhoea, and retinopathy), lithium (e.g., tremors, increased urination, diarrhea, and possible kidney damage), and verapamil (as described above).
Intravenous administration of lidocaine has been shown to demonstrate a limited benefit over placebo in the treatment of acute migraines, but has failed to demonstrate clinically significant efficacy (Reutens, et al., Cephalalgia, 11(6):245-247, 1991). Intranasal administration of local anesthetics, such as lidocaine, for the relief of migraine pain has also been explored as a treatment option. However, studies investigating lidocaine treatment indicate that there can be a low rate of efficacy (Kudrow et al., Headache, 35:79-82, 1995), or that patients experience relapses of pain soon after treatment and/or suffer from pronounced local adverse events (Maizels et al., J. Amer. Med. Assoc. 276:319-321, 1996). In addition, lidocaine has been associated with serious side-effects such as methemoglobinemia (Guay, Anesth Analg., 108(3):837-45, 2009) and toxic metabolic byproducts such as 2,6-xylidine and 4-hydroxyxylidine (as is common for amide-based anesthetics). Treatment with other local anesthetics have also met with disappointing results.
Other procedures have been recommended to decrease the frequency of headaches. In the context of migraines, such procedures include surgery, counseling, and participation in biofeedback procedures. In the context of cluster headaches, such procedures include surgery, implantation of devices to stimulate the occipital nerve, and implantation of stimulators in the hypothalamus. However, the efficacy of these treatments is debated and some, such as surgery, carry the risk of serious side effects.
Because the currently available treatments for headaches suffer from varying degree of effectiveness, length of efficacy, and/or lack of consistency of efficacy, there remains a need for effective and safe headache treatments which preferably provide increased length of efficacy.